Acquired Immune Deficiency Syndrome(AIDS) is believed to be caused by the HIV family of retroviruses as well as other still un-identified factors. The virion or its envelop protein, gp120, binds to the CD4 molecule on the surface of CD4+ immune cells to gain entry. Its gene, an RNA, is transcribed to DNA by its Reverse Transcriptase(RT), and it is integrated into the host cell genome, becoming a part of the host cell.
When the infected cell is activated, the guest genome is also replicated. The HIV protein, Tat, is required for the HIV transcription. Blockage of Tat inhibits HIV replication in acute and chronic infection.
During the latency period of eight years on the average, the helper T4 lymphocytes, whose function is to mount a cellular immune defense against foreign invaders, die off slowly, exposing the host to various bacterial infections, and eventually, through a not-yet-well-known mechanism, causing damage to the brain and the central nervous system. Infected lymphocytes secrete Tat and an oncoprotein, which drive tumorigenesis/angiogenesis in AIDS-associated Kaposi's sarcoma(KS).
The only drug which has been found to be useful clinically is AZT, a nucleoside, which is a chain terminator in the transcription. Its clinical benefit is still not definitively established: it develops drug resistance by mutating the RT and also its toxicity to the host is severe. Combination therapy using mixed nucleosides at lower doses is the current practice, without proven efficacy.
This has occasioned an intense search for non-nucleoside and non-protein/peptide drugs. Recently, diazepines have been found to be active against RT and Tat. Inhibitors of the HIV protease have also been developed. But, none have reached the market. Some diazepine analogues, however, are well-known psychotrophic and neurotrophic compounds. One of the side effects has been immunodeficiency, which caused multiple deaths before it was recognized.